1. Field of the Invention
The present invention relates generally to the fields of medical physics and drug delivery. More specifically, the present invention relates to a method of continuous delivery of pharmaceutical compounds using electromagnetic energy.
2. Description of the Related Art
Various methods have been used for facilitating the delivery of compounds across the skin and other membranes. lontophoresis uses an electric current to increase the permeation rate of charged molecules. However, iontophoresis is dependent on charge density of the molecule and has further been known to cause burning in patients. Use of ultrasound has also been tested whereby application of ultrasonic energy to the skin results in a transient alteration of the skin, which leads to an increased permeability to substances. Electromagnetic energy produced by lasers may be used to ablate stratum corneum in order to make the skin more permeable to pharmaceutical substances (U.S. Pat. No. 4,775,361), and impulse transients generated by lasers or by mechanical means may be used to make alterations in epithelial layers that result in improved permeation of compounds (U.S. Pat. No. 5,614,502).
Skin has a very thin layer of dead cells, called the stratum corneum, which acts as an impermeable layer to matter on either side of the layer. The stratum corneum primarily provides the skin""s barrier function. If the stratum corneum is removed or somehow altered, materials can more easily diffuse into or out of the skin. Alternatively, compounds referred to as permeation enhancers (e.g. alcohol) or drug carriers (e.g. liposome) can be used, with some success, to penetrate the stratum corneum. In any case, the barrier function of the skin presents a very significant problem to pharmaceutical manufacturers who may be interested in topical administration of drugs, or in cutaneous collection of bodily fluids.
Mucosa, the moist lining of many tubular structures and cavities (e.g. nasal sinuses and mouth), consists in part of an epithelial surface layer. This surface layer consists of sheets of cells in single or multiple layers with strong intercellular bonds, and has a non-keratinized or keratinized epithelium. On the basolateral side of the epithelium is a thin layer of collagen, proteoglycans and glucoproteins called the basal lamina, which serves to bind the epithelial layer to the adjacent cells or matrix. The mucosa acts as a barrier to prevent the significant absorption of topically applied substances, as well as the desorption of biomolecules and substances from within the body. The degree to which mucosa acts as a barrier, and the exact nature of the materials to which the mucosa is impermeable or permeable, depends on the anatomical location. For example, the epithelium of the bladder is 10,000 times less xe2x80x9cleakyxe2x80x9d to ions than the intestinal epithelium.
The mucosa is substantially different from skin in many ways. For example, mucosa does not have a stratum corneum. Despite this difference, permeation of compounds across mucosa is limited and somewhat selective. The most recent model of the permeability of mucosa is that the adjacent cells in the epithelium are tightly bound by occluding junctions, which inhibit most small molecules from diffusing through the mucosa, while allowing effusion of mucoid proteins. The molecular structure of the epithelium consists of strands of proteins which link together between the cells, as well as focal protein structures such as desmosomes. The permeation characteristics of mucosa are not fully understood, but it is conceivable that the selective permeability of the mucosa may depend on its epithelial layer as well as the basal lamina. While it has been shown that removal or alteration of the stratum corneum of skin can lead to an increase in skin permeability, there is no corresponding layer on the mucosa to modify.
There are methods on transdermal drug delivery enhancements using laser ablation or alteration of stratum corneum. More recent technology involves using shock waves to make stratum corneum and cell walls more permeable. One of the problems with the available methods of drug delivery enhancement is that the tissue is altered transiently to be made permeable. Furthermore, there is little or no control over the degree of tissue alteration, and no control over how much drug is delivered.
The prior art is deficient in the lack of effective means of improving the permeation rates of pharmaceutical compounds across biological membranes, e.g. mucosa and skin. Specifically, the prior art is deficient in the lack of effective means of enhancing drug delivery by utilizing non-ionizing electromagnetic energy. The present invention fulfills this long-standing need and desire in the art.
The present invention describes methods and apparatus for improving the permeation rates of pharmaceutical compounds across biological membranes. Also provided is a method for increasing the diffusion of substances out of tissue.
The present invention uses electromagnetic energy including radiofrequency energy to create propagating pressure waves. These pressure waves can be used to push the drug molecules into the skin or other membranes, or push biomolecules out of the skin. This method allows for continuous and controllable transmembrane drug delivery. In the presence of propagating pressure waves, molecules in a mobile phase (e.g. the drug) would be pushed in the direction of wave propagation while the static phase (e.g. the tissue) would maintain it""s position.
In one embodiment of the present invention, there is provided a method for enhancing continuous delivery of a pharmaceutical compound in a subject, comprising the steps of irradiating the subject with electromagnetic energy continuously; and applying the pharmaceutical compound to the subject. The pharmaceutical compound interacts with the electromagnetic energy. Examples of electromagnetic energy include radiofrequency and microwave. Pharmaceutical compound can be an anesthetic drug, an antineoplastic drug, a photodynamic therapeutical drug or any other drug that can interact with electromagnetic energy and be propelled through subject""s barrier.
In another embodiment of the present invention, there is provided a method for increasing diffusion rate of a substance in a medium, comprising the step of applying electromagnetic energy to the medium, wherein the electromagnetic energy generates propagating pressure wave upon the medium. The medium can be a liquid or semi-solid medium.
In still another embodiment of the present invention, there is provided a method for improving permeation rate of a molecule through a barrier, comprising the step of applying electromagnetic energy to the barrier, wherein the electromagnetic energy ablates or alters the structure of the barrier. The barrier can be biological and non-biological. Examples of biological barrier include skin, vaginal wall, uterine wall, intestinal wall, buccal wall, tongue, nasopharyngeal wall, anal wall, bladder wall, vascular vessel, lymphatic vessel and urethral vessel.
In yet another embodiment of the present invention, there is provided a method for creating pores in a barrier thereby improving permeation rate of a molecule through the barrier, comprising the step of applying electromagnetic energy with a probe to the barrier, wherein the probe conducts the electromagnetic energy. Specifically, the probe is made of silicon with a metallic conducting material.
In still yet another embodiment of the present invention, there is provided a method for enhancing continuous delivery of a pharmaceutical compound in a subject, comprising the steps of treating the subject to weaken the barrier function of its membrane first; irradiating the pre-treated subject with electromagnetic energy continuously; and applying the pharmaceutical compound to the subject. The subject can be pre-treated with electromagnetic energy, or using other membrane-weakening method.
Further provided in the present invention is a system for enhancing continuous delivery of a pharmaceutical compound in a subject, comprising a means to generate electromagnetic energy; a means to deliver the electromagnetic energy to the subject continuously; and a means to administer the pharmaceutical compound to the subject. Preferably, the system further comprises a probe which is delivered to the subject at the same time as the electromagnetic energy. Specifically, the probe is made of a magnetic material, such as a metal.
Other and further aspects, features, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention given for the purpose of disclosure.
The present invention discloses methods to make targets associated with tissue interfaces permeable to diagnostic and therapeutic substances. The invention uses non-ionizing electromagnetic energy to increase the diffusion rate of substances into or out of tissues. These methods, referred to as xe2x80x9celectromagnetic energy-enhanced deliveryxe2x80x9d, involve the transient or sustained alteration of membranes and tissue interfaces caused by electromagnetic energy including wavelengths much longer than those of light. The electromagnetic energy described herein is often referred to as microwave and radiofrequency.
There are a variety of aspects of continuous delivery of pharmaceutical compounds across membranes using electromagnetic energy. In one aspect, propagating pressure waves are used to create pressure in a medium such that the diffusion rate of the substances in the medium (usually a drug formulation) is increased relative to its surrounding environment. In a related aspect, these pressure waves are used to create transient alterations in the membrane or tissue. Alternatively, a trap is formed which generates a electromagnetic dipole in the tissue. Movement of this trap relative to the substance creates an electromagnetic gradient, which essentially xe2x80x9cpullsxe2x80x9d the molecules along. Electromagnetic energy used to ablate or alter molecular structures in the skin or mucosa is discussed as a means of xe2x80x9copeningxe2x80x9d pores to further improve permeation rates of molecules. Electromagnetic energy can also be used to ablate or alter skin or membranes thus reducing their barrier function and providing a way for molecules to diffuse. Some of these aspects might benefit from a molecular alteration of the pharmaceutical being delivered; therefore some specific drug formulations were tried for use in conjunction with electromagnetic energy.
Enhancement of drug delivery can take place with the use of osmotic or atmospheric pressure (applied, for example, in the form of a patch over the site of irradiation). A patch of distilled water in contact with the treated skin would enhance the diffusion of glucose out of the skin due to osmotic pressure. A patch which positions a drug in intimate contact with the skin or mucosa, and has an adjacent chamber with an increased pressure would tend to push the drug into the tissue.
There are many therapeutic and diagnostic procedures that would benefit from a transmucosal or transendothelial route of administration or collection. For example, it is a specific object of the present invention to describe methods and devices for delivery of local anesthetics, such as lidocaine, to a region prior to a medical treatment. Such a local administration of lidocaine could be efficacious at providing anesthesia, but would minimize any side-effects and eliminate the need for a needle. Local administration of an antineoplastic drug into the bladder wall could greatly minimize the time required for a patient to hold a drug in the bladder during chemotherapy.
Electrosurgery, which is a method whereby tissue coagulation and/or dissection can be effected, provides insight into the present invention. In electrosurgery, radiofrequency (RF) current is applied to tissue by an active electrode. In a bipolar system, the current is passed through tissue between two electrodes on the same surgical instrument, such as a forceps. In a monopolar system, a return-path (ground) electrode is affixed in intimate electrical contact with some part of the patient. Because of the importance of the ground electrode providing the lowest impedance conductive path for the electrical current, protection circuits monitoring the contact of the ground with the patient are often employed wherein an increase in ground electrode-skin impedance results in the instrument shutting down. Depending on treatment electrode shape, electrode position (contact or non-contact) with respect to the tissue surface, frequency and modulation of the radiofrequency, power of the RF and time for which it is applied to the tissue surface, peak-to-peak voltage of the radiofrequency, and tissue type, one may obtain desirable effects including cutting and coagulation of tissue. In a typical electrosurgical systems, radiofrequency frequencies of 300 kHz to 4 MHz are used since nerve and muscle stimulation cease at frequencies beyond 100 kHz.
For example, decreasing electrode size translates into increased current density in the tissue proximal to the electrode and so a more invasive tissue effect, such as dissection as compared to coagulation. Similarly, if the electrode is held close to the tissue but not in contact, then the area of radiofrequency-tissue interaction is smaller as compared to that when the electrode is in contact with the tissue, therefore, the effect on the tissue is more invasive. By changing the waveform of the applied radiofrequency from a continuous sinusoid to packets of higher peak voltage sinusoids separated by dead time (i.e. a duty cycle of 6%), then the tissue effect can be changed from dissection to coagulation. Increasing the voltage of the waveform increases the invasiveness of the tissue effect, and the longer the tissue is exposed to the radiofrequency, the greater the tissue effect. Finally, different tissues respond to radiofrequency differently because of their different electrical conductive properties, concentration of current carrying ions, and different thermal properties.
In the present invention, the following terms have the definitions set below.
As used herein, xe2x80x9cdipole forcexe2x80x9d shall refer to a force which results when a molecule moves in order to achieve a more stable dipole state.
In one embodiment of the present invention, there is provided a method for enhancing continuous delivery of a pharmaceutical compound in a subject, comprising the steps of irradiating the subject with electromagnetic energy continuously; and applying the pharmaceutical compound to the subject. The pharmaceutical compound interacts with the electromagnetic energy. Examples of electromagnetic energy include radiofrequency, microwave and light. The pharmaceutical compound can be an antibiotics, cytokines, bone vascularization enhancers, anesthetic drugs, antineoplastic drugs, photodynamic therapeutical drugs, anti-infection drugs and anti-inflammatory drugs or any other drug that can interact with electromagnetic energy and be propelled through subject""s barrier. A specific example of anesthetic drug is lidocaine.
In another embodiment of the present invention, there is provided a method for increasing diffusion rate of a substance in a medium, comprising the step of applying electromagnetic energy to said medium, wherein said electromagnetic energy generates propagating pressure wave upon said medium. The electromagnetic energy may be radiofrequency, microwave and light. The medium can be a liquid or semi-solid medium
In still another embodiment of the present invention, there is provided a method for improving permeation rate of a molecule through a barrier, comprising the step of applying electromagnetic energy to the barrier, wherein the electromagnetic energy ablates or alters the structure of the barrier. The electromagnetic energy may be radiofrequency, microwave and light. The barrier can be biological and non-biological. Examples of biological barrier include skin, vaginal wall, uterine wall, intestinal wall, buccal wall, tongue, nasopharyngeal wall, anal wall, bladder wall, vascular vessel, lymphatic vessel and urethral vessel. Representative examples of non-biological barrier include a non-biological membrane, film and gel.
In yet another embodiment of the present invention, there is provided a method for creating pores in a barrier thereby improving permeation rate of a molecule through the barrier, comprising the step of applying electromagnetic energy with a probe to the barrier, wherein the probe conducts the electromagnetic energy. Specifically, the probe is made of a magnetic material, for example, silicon with a metallic conducting material.
In still yet another embodiment of the present invention, there is provided a method for enhancing continuous delivery of a pharmaceutical compound in a subject, comprising the steps of treating the subject to weaken the barrier function of its membrane first; irradiating the pre-treated subject with electromagnetic energy continuously; and applying the pharmaceutical compound to the subject. The electromagnetic energy may be radiofrequency, microwave and light. The subject can be pre-treated with electromagnetic energy, or using other membrane-weakening methods.
Further provided in the present invention is a system for enhancing continuous delivery of a pharmaceutical compound in a subject, comprising a means to generate electromagnetic energy; a means to deliver the electromagnetic energy to the subject continuously; and a means to administer the pharmaceutical compound to the subject. Preferably, the system further comprises a probe which is delivered to the subject at the same time as the electromagnetic energy. Specifically, the probe is made of a magnetic material, such as a metal or the probe is made of silicon with a metallic conducting material. The energy is selected from the group consisting of radiofrequency, microwave and light. A representative pharmaceutical compound is an anesthetic drug.